CNS5:Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
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Primary Author(s)*
Madina Sukhanova, PhD, FACMG Northwestern University
Cancer Category/Type
Glioneuronal tumour
Cancer Sub-Classification / Subtype
Paediatric-type diffuse high-grade gliomas with three molecular subtypes: RTK2, RTK1, and MYCN
Definition / Description of Disease
This is a distinct entity in the World Health Organization (WHO) classification system within the section of paediatric-type diffuse high-grade gliomas. Distinct methylation profiles and molecular alterations define three subtypes: dpHGG RTK1, dpHGG RTK2, and dpHGG MYCN. Gliomas arising after therapeutic radiation are predominantly of the pHGG RTK1 subtype. Known tumorigenic drivers include TP53, MYCN, ID2, and genes from RAS/MAPK and PI3K pathways.[1] [2] [3] [4]
Synonyms / Terminology
None
Epidemiology / Prevalence
The 2021 WHO classified this entity as pediatric-type based on well defined studies characterized by negative molecular features of H3 and IDH [4][5][6] which have focused only on pediatric patients; thus, the frequency of this tumor type in adults in unknown. Median reported age of patients at the time of diagnosis was 9.8 years. One study reported male prevalence.[6]
Clinical Features
The clinical features are dependent on the tumour location. Symptoms can include seizures and motor or sensory deficits.
| Signs and Symptoms | Seizures and motor or sensory deficits. |
| Imaging Findings | MRI characteristics are comparable to other high-grade glioma tumour types. MRI typically reveals well-defined margins and homogeneous contrast-enhancement and mild perilesional edema.[7][8] |
Sites of Involvement
Main site: supratentorial brain.
Other sites: brainstem, and cerebellum.[6]
Although most of molecular subtypes of dpHGG involve supratentorial brain (96% of dpHGG RTK2, 86% of dpHGG MYCN, and 82% of dpHGG RTK1 tumors), 4% of dpHGG RTK2, 14% of dpHGG MYCN, and 18% of dpHGG RTK1 cases can involve infratentorial/brainstem sites.[6]
Morphologic Features
Morphology of dHGGs, H3-/IDH-wildtype, is consistent with glioblastoma-like features with high cellularity, mitotic activity, microvascular proliferation, and necrosis; however, undifferentiated morphology and areas of glial differentiation can also be noted. pHGG MYCN molecular subtype often consists of large cells with distinct nucleoli, spindle-shaped and epithelioid cells and also reveals areas of diffuse infiltration and circumscribed nodules.[7]
Immunophenotype
| Finding | Marker |
|---|---|
| Positive (universal) | Neoplastic glial component – GFAP, and/or OLIG2.[3][4] |
| Positive (subset) | dpHGG MYCN molecular subtype can be positive for neuronal markers. |
| Negative (universal) | IDH1 R132H (normal retained pattern of staining).
H3 p.K28me3 (K27me4) (preserved expression).[7] |
| Negative (subset) | dpHGG MYCN molecular subtype can be negative for glial marker GFAP, and/or OLIG2. |
Chromosomal Rearrangements (Gene Fusions)
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE t(9;22)(q34;q11.2) | EXAMPLE 3'ABL1 / 5'BCR | EXAMPLE der(22) | EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference) |
Yes | No | Yes | EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
Individual Region Genomic Gain/Loss/LOH
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| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE
7 |
EXAMPLE Loss | EXAMPLE
chr7:1- 159,335,973 [hg38] |
EXAMPLE
chr7 |
Yes | Yes | No | EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE
8 |
EXAMPLE Gain | EXAMPLE
chr8:1-145,138,636 [hg38] |
EXAMPLE
chr8 |
No | No | No | EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference). |
Characteristic Chromosomal Patterns
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| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
Gene Mutations (SNV/INDEL)
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| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
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Genes and Main Pathways Involved
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
Genetic Diagnostic Testing Methods
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Familial Forms
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Additional Information
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Links
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References
- ↑ Buczkowicz, Pawel; et al. (2014-05). "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics. 46 (5): 451–456. doi:10.1038/ng.2936. ISSN 1546-1718. PMC 3997489. PMID 24705254. Check date values in:
|date=(help) - ↑ Sturm, Dominik; et al. (2016-02-25). "New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs". Cell. 164 (5): 1060–1072. doi:10.1016/j.cell.2016.01.015. ISSN 1097-4172. PMC 5139621. PMID 26919435.
- ↑ 3.0 3.1 Korshunov, Andrey; et al. (2015-05). "Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers". Acta Neuropathologica. 129 (5): 669–678. doi:10.1007/s00401-015-1405-4. ISSN 1432-0533. PMID 25752754. Check date values in:
|date=(help) - ↑ 4.0 4.1 4.2 Mackay, Alan; et al. (2017-10-09). "Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma". Cancer Cell. 32 (4): 520–537.e5. doi:10.1016/j.ccell.2017.08.017. ISSN 1878-3686. PMC 5637314. PMID 28966033.
- ↑ Mackay, Alan; et al. (2018-05-14). "Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial". Cancer Cell. 33 (5): 829–842.e5. doi:10.1016/j.ccell.2018.04.004. ISSN 1878-3686. PMC 5956280. PMID 29763623.
- ↑ 6.0 6.1 6.2 6.3 Korshunov, Andrey; et al. (2017-09). "H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers". Acta Neuropathologica. 134 (3): 507–516. doi:10.1007/s00401-017-1710-1. ISSN 1432-0533. PMID 28401334. Check date values in:
|date=(help) - ↑ 7.0 7.1 7.2 Tauziède-Espariat, A.; et al. (2020-07-09). "The pediatric supratentorial MYCN-amplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts". Acta Neuropathologica Communications. 8 (1): 104. doi:10.1186/s40478-020-00974-x. ISSN 2051-5960. PMC 7346460 Check
|pmc=value (help). PMID 32646492 Check|pmid=value (help). - ↑ Tauziède-Espariat, A.; et al. (2019-06-10). "An integrative radiological, histopathological and molecular analysis of pediatric pontine histone-wildtype glioma with MYCN amplification (HGG-MYCN)". Acta Neuropathologica Communications. 7 (1): 87. doi:10.1186/s40478-019-0738-y. ISSN 2051-5960. PMC 6556947. PMID 31177990.
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EXAMPLE Book
- Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
Notes
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